Tumor Necrosis Factor (TNF)-family members can best be described as master switches in the immune system controlling both cell survival and differentiation. Given the current progress in manipulating members of the TNF-family for therapeutic benefit, including anti-tumor activity as well as immune regulation and inflammation, it is likely that members of this family will provide unique means to control disease. The medical utility of the TNF ligands and antagonists to the ligands has been shown for several systems. Most notable is TNF. TNF controls a wide array of immune processes, including inducing acute inflammatory reactions, as well as maintaining lymphoid tissue homeostasis. Because of the dual role this cytokine can play in various pathological settings, both agonist and antagonist reagents have been developed as modifers of disease. For example TNF and LTα (which also signals through the TNF receptors) have been used as a treatment for cancers, especially those residing in peripheral sites, such as limb sarcomas. In this setting direct signaling by the cytokine through the receptor induces tumor cell death (Aggarwal and Natarajan, 1996. Eur Cytokine Netw 7:93-124). In immunological settings agents which block TNF receptor signaling (eg., anti-TNF mAb, soluble TNF-R fusion proteins) have been used to treat diseases like rheumatoid arthritis and inflammatory bowel disease. In these pathologies, TNF is acting to induce cell proliferation and effector function, thereby exacerbating autoimmune disease. In this setting blocking TNF binding to its receptor(s) has therapeutic benefit (Beutler, 1999. J Rheumatol 26 Suppl 57:16-21).
A more recently discovered ligand/receptor system appears amenable to similar manipulations. Lymphotoxin beta (LTβ), a TNF family member which forms heterotrimers with LTα, binds to the LTβ-R. Some adenocarcinoma tumor cells which express LTβ-R can be killed or differentiated when treated with an agonistic anti-LTβ-R mAb (Browning et al., 1996. J Exp Med 183: 867-878). In immunological settings it has been shown that anti-LTβ mAb or soluble receptor fusion protein LTβ-R-Ig can block the development of inflammatory bowel diseases, possibly by influencing dendritic cell and T cell interaction (Mackay et al., 1998. Gastroenterology 115:1464-1475).
In addition to the TNFR and LTβ-R systems, manipulation of the TRAIL (Gura, 1997. Science 277: 768) and OPG (Simonet et al. 1997. Cell 89: 309-319) pathways may be therapeutically beneficial in treating cancer and bone loss, respectively. Recently, through database searches, there has been a number of newly described members of the TNF family of ligands and receptors. In addition to the number of new members, the complexity of the ligand/receptor interactions has also increased. It is now apparent that the TNF and LT systems are not unique in the ability of the ligand to interact with more than one receptor. Among the ligands reported to bind more than one receptor or receptor decoy are FasL, TRAIL, RANKL, and LIGHT.
Thus, there is a clear need to identify and characterize additional molecules which are members of the TNF family thereby providing additional means of controlling disease and manipulating the immune system.